Currently there are numerous controlled release formulations on the market that contain various bioactive agents, such as GnRH analogs, human growth hormone, risperidone and somatostatin analogs of which octreotide acetate is an example. These controlled release compositions are typically formulated with biodegradable, biocompatible polymers. Such formulations are preferred by healthcare professionals and their patients because they reduce the need for multiple injections. Additionally, since one injection treats a patient for a prolonged period of time, health care organizations prefer them because they decrease the number of office visits per patient, which works to decrease health care costs.
Unfortunately, there are many problems with the current production processes and formulations for controlled release compositions. Many current manufacturing processes are incapable of producing concentrated product exhibiting a high drug load, thus necessitating a large intramuscular injection volume (2 mL) that is quite uncomfortable for the patient when administered. Additionally, many methods require time consuming and complex procedures to solubilize bioactive agents prior to encapsulation; and manipulation of solubility for purposes of encapsulation can result in deleterious release profiles, as well as degradation of the bioactive agent itself. For example, the use of highly water soluble bioactive agents frequently results in an undesirable “burst” of bioactive agent upon contact with an aqueous solution, such as by administration to a patient or introduction to a physiological medium. Such a rapid rise in levels of bioactive agent can be detrimental to a patient and may leave little bioactive agent for later release over the desired treatment time course.
Various methods of solving the solubility problem have been attempted but none have been particularly efficient or effective. One such attempt combined a bioactive agent with a surfactant molecule, comprising an anionic head and a hydrophobic tail, to solubilize the bioactive agent in an organic phase prior to encapsulation. Another method combined organic acids with the bioactive agent to produce a water insoluble addition salt prior to encapsulation. The use of an insoluble additional salt resulted in a lessening of the “burst” effect upon administration; however, this method required additional manufacturing procedures that made production of these compounds expensive and inefficient. Another method included encapsulation of the acetate salt of the bioactive agent that resulted in substantial amounts of chemically modified or degraded bioactive agent being released after placement in an aqueous physiological buffer. Chemical degradation was in the form of undesirable acylation of the bioactive agent.
Methods of producing controlled release compositions that are capable of producing a product with a high drug load, minimum burst effect upon administration and minimum degradation of the bioactive agent are greatly needed to realize the true benefits of these types of compositions as human or veterinary therapeutics.